The present invention relates generally to spin-order transfer and in particular to methods and apparatus for preparation of spin-polarized reagents. Such reagents can be used, for example, in nuclear magnetic resonance (NMR) experiments. The methods and apparatus described herein can be applied to any reagent of biological interest and provide hyperpolarized samples of the reagent as described below.
Since the inception of NMR over sixty years ago, the basic strategy of the vast majority of experiments is unchanged. The sample is placed in the highest available homogeneous field, spin-lattice relaxation allows attainment of the weak equilibrium alignment of the nuclear spins (e.g., a fractional polarization P=10−5 for carbon-13 (13C) in a magnetic field of 1.5 tesla (T) at room temperature), and Faraday-law inductive detection is used to detect the precessing magnetization induced at the Larmor frequency of the target spins by radio-frequency (RF) irradiation. Despite the sensitivity improvements due to the separate linear increases of both polarization and induced voltage with magnetic field, the fact remains that all routine experiments are performed with polarizations at the part-per-million polarization level. The result is that for the great majority of situations in biology, where the noninvasiveness and chemical specificity of NMR would seemingly make it the method of choice, NMR is instead impractical due to low sensitivity.
For essentially all NMR and MRI experiments in use, the sensitivity is proportional to the fractional polarization P of the target spins. It is remarkable that NMR has contributed so much to our understanding of the brain and other organs using only part-per-million polarizations. That MRI is possible at all is due to slight variations in the density or relaxation times of the highly concentrated (˜80 M) water protons. The in vivo study of metabolism with 1H or 13C/15N NMR with equilibrium spin polarization has been possible only with little or no spatial localization and prolonged signal averaging that largely precludes the study of dynamics and is severely limited by cost. Thus, there has been considerable interest in finding ways to increase the fractional polarization in target molecular species of biological interest.
For example, the PASADENA method (see, e.g., [1][[2][3]) can be used to hyperpolarize molecules that can be formed by molecular addition of dihydrogen. PASADENA is unique in achieving nuclear spin polarizations of order unity within seconds at liquid-state temperatures [3][4][5][6][7]. Studies of biological applications of this method are underway. However, for the great majority of molecules of interest as metabolites, drugs, or biopolymers, PASADENA is inapplicable for lack of suitable chemistry.
Another method, dynamic nuclear polarization (DNP), uses electron spin resonance (ESR) irradiation of paramagnetic impurities at temperatures of a few K [8]. DNP methods have recently been improved, and the hyperpolarized products can be rapidly warmed and dissolved for liquid-state studies [5][9][10][11][12][13][14]. Polarization of 13C and 15N sites in several small molecules has been reported, and in principle this method is generally applicable. In order to reach fractional polarizations of order unity, the sample must be irradiated with microwaves in a dedicated high field magnet (>3 T) at a temperature of about 2 K for several hours prior to rapid melting and dissolution. Nevertheless, the technology has been commercialized, and its success is an indication of the wide recognition in the biomedical community of the potential for hyperpolarized MRI. Of particular interest as a proof of principle for metabolic imaging are the in vivo observation of several hyperpolarized daughter metabolites of 13C-labeled pyruvate [11][12] and their variation in rate of production with disease state.